TR201807704T4 - Anti-viral treatment. - Google Patents

Abstract

The present invention relates to combinations of compounds comprising HIV integrase inhibitors and other therapeutic agents. Such combinations are used to inhibit HIV replication, to prevent and / or treat HIV infection, and to treat AIDS and / or ARC.

Description

DESCRIPTION ANTI-VIRAL THERAPY BACKGROUND OF THE INVENTION Human immunodeficiency Virus ("HIV") is the causative agent for acquired immunodeficiency syndrome ("AIDS"), a disease characterized by destruction of the immune system, particularly CD4+ T-cells, accompanied by susceptibility to opportunistic infections, and for AIDS-associated precursor complex ("ARC"), a syndrome characterized by symptoms such as persistent generalized lymphadenopathy, fever, and weight loss. HIV is a retrovirus; the conversion of its RNA to DNA is mediated by the action of the enzyme reverse transcriptase. Compounds that inhibit the function of reverse transcriptase inhibit HIV replication in infected cells. These compounds are used in the prevention or treatment of HIV infection in humans. In addition to CD4, HIV requires a co-receptor for entry into target cells. Chemokine receptors work with CD4 as co-receptors for HIV. Chemokine receptors CXCR4 and CCRS have been identified as the major co-receptors for HIV-1. CCRS functions as a major co-receptor for the fusion and entry of macrophage-trophic HIV into host cells. These chemokine receptors are thought to play a central role in the establishment and spread of an HIV infection. Therefore, CCR5 antagonists are considered useful as active therapeutic agents against HIV. As with several other retroviruses, HIV encodes the production of a protease that carries out post-translational cleavage of precursor polypeptides in a process required for the formation of infectious virions. These gene products include the virion RNA-dependent DNA polyubiquinone (reverse transcriptase) encoding polyubiquinone, an endonuclease, the HIV protease, and the virion core protein encoding the virion. One focus of antiviral design has been to generate compounds that inhibit the assembly of infectious virions by interfering with the processing of viral polyprotein precursors. Processing of these precursor proteins requires the activity of the virally encoded protease, which is required for replication. The antiviral potential of HIV protease inhibition has been demonstrated using peptidyl inhibitors. An essential step in HIV replication in human T cells is the insertion of the virally encoded integrase of the proviral DNA into the host cell genome. Integration involves: The assembly of a stable nucleoprotein complex with viral DNA sequences, the cleavage of two nucleotides from the 3' terminus of linear proviral DNA, and the covalent attachment of the buried 3' OH terminus of proviral DNA to a cross-section created at the host target site are thought to be mediated by integrase. Repair synthesis of the resulting gap may be accomplished by cellular enzymes. HIV integrase inhibitors may be effective in treating AIDS and inhibiting viral replication. The use of combinations of therapeutic compounds in the treatment of HIV infection and related conditions may result in increased antiviral efficacy, decreased toxicity, delayed progression of resistance, and increased drug efficacy. Combinations administered in a single dosage unit may provide increased patient compliance by reducing pill burden and simplifying dosage schedules. However, not all compounds are suitable for administration in combinations. Factors affecting the suitability of combinations include chemical instability of the compounds, dosage unit size, antagonistic potential or merely additive activities of the combined compounds, and difficulties in obtaining a suitable formulation. There is a continuing need to find therapeutic agents and feasible pharmaceutical compositions suitable for use in combination to treat HIV infection. Because of their high potency and pharmacokinetic profiles, certain HIV integrase inhibitors are attractive as components in combination therapy. The use of GSK1349572 (dolutegravir) in the treatment of HIV is described in "A Phase IIb Pilot Study to Assess the Antiviral Activity of GSK 1349572 Containing Regimen in Antireteroviral Therapy (ART)-Experienced, HIV-1-infected Adult Subjects With Raltegravir Resistance", January 2010. WO 2009/007441 describes a crystalline form of TCM278 (rilpivirine) and its use in the treatment of HIV infection. BRIEF DESCRIPTION OF THE FIGURES Reference Figure 1: Inhibition of HIV-lllB by a compound represented by formula (I), GSK1349572A, in combination with abacavir (ABC). Reference Figure 2: Inhibition of HIV-lllß by a compound represented by formula (I), GSK1349572A, in combination with efavirenz (EFV). Reference Figure 3: Inhibition of HIV-lllß by a compound represented by formula (I), GSK1349572A, in combination with lopinavir (LPV). SUMMARY OF THE INVENTIONThe present invention relates to a combination comprising a compound represented by formula (I), or a pharmaceutically acceptable salt thereof, and rilpivirine or a pharmaceutically acceptable salt thereof. The combination is used in inhibiting HIV replication, preventing and/or treating HIV infection, and treating AIDS and/or ARC. The present invention is defined in the appended claims. Subjects not covered by the claims do not form part of the present invention. DETAILED DESCRIPTION OF THE INVENTION The present invention relates to compositions comprising a compound represented by the following formula (I), (II), or (III): F(ui) or a pharmaceutically acceptable salt thereof, and one or more therapeutic agents selected from the group consisting of nucleotide reverse transcriptase inhibitors, nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors, CCR5 antagonists, CXCR4 antagonists, fusion inhibitors, maturation inhibitors, and integrase inhibitors. The present invention relates to a combination comprising a compound represented by formula (I), (II), or a pharmaceutically acceptable salt thereof, and rilpivirine or a pharmaceutically acceptable salt thereof. The present invention relates to the treatment of HIV infection, AIDS and AIDS-related conditions by administering to a subject a compound represented by formula (I), (II), or (111) and one or more therapeutic agents selected from the group consisting of nucleotide reverse transcriptase inhibitors, nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors, CCRS antagonists, CXCR4 antagonists, fusion inhibitors, maturation inhibitors and integrase inhibitors. A compound represented by formula (1) is also known as GSK1349572. A chemical name of the compound represented by the formula (1) is (4R, 12aS)-N-[(2,4-difluorophenyl)methyl]-3,4,6,8,12,1Za-hexahydro-7-hydroxy-4-methyl-6,8-dioxo-ZH-pyrido[1,2,:4,5]pyrizone[2,1-b][1,3]oxazine-9-carboxamide. A chemical name of the compound represented by the formula (H) is (38, 11AR)-N-[(2,4-difluorophenyl)methyl]-2,3,5,7,11,11a-hexahydro-o-hydroxy-3-methyl-5,7-dixo-oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide. A chemical name of the compound represented by the formula (111) is (38, 11AR)-N-[(2,4-difluorophenyl)methyl]-2,3,5,7,11,11a-hexahydro-o-hydroxy-3-methyl-5,7-dixo-oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide. A chemical name for the compound represented is (4aS,13aR)-N-[(2,4-diphenoxy-9,11-dioxo-2,3,4a,5,9,11,13,13a-octahydro-1H-pyrid0[1,2-a]pyrrolo[132":3,4]imidazole[1,2-d]pyrazine-8-carboxamide. A "pharmaceutically acceptable carrier or adjuvant" refers to a carrier or adjuvant that can be administered to a patient in conjunction with a compound of the invention and that does not interfere with the pharmacological activity of the compound and is nontoxic when administered in doses sufficient to deliver a therapeutic amount of the antiviral agent. As used herein, the term "treatment" means any agent that alleviates the symptoms of a particular disease in a patient. refers to the reduction of, or amelioration of, an assayable measure associated with a particular condition, and may include suppressing the recurrence of a symptom in an asymptomatic patient, such as a patient in whom a viral infection has become latent. Treatment may include prophylaxis, which refers to the prevention of, or the prevention of the development of, symptoms of a disease or condition in a patient. As used herein, the term "patient" refers to a mammal, including a human. As used herein, the term "subject" refers to a patient, animal, or a biological specimen. Pharmaceutically acceptable salts of the compounds of the invention include those derived from pharmaceutically acceptable inorganic and organic acids and bases. Examples of suitable acids include hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic, toluene-p-sulfonic, tartaric, acetic, citric, methanesulfonic, ethanesulfonic, formic, benzoic, malonic, naphthalene-Z-sulfonic and benzene-sulfonic acids. Other acids, such as oxalic acid, although not themselves pharmaceutically acceptable, can be used in the preparation of useful salts as intermediates for the preparation of compounds of the invention and their pharmaceutically acceptable addition salts. Salts obtained with suitable bases include alkali metal (e.g. sodium), alkaline earth metal (e.g. magnesium), ammonium, NW4+ (where W is C1-4 alkyl) and other amine salts. An advantageous salt is the sodium salt. Salts of the compounds of the present invention can be produced by methods known to a person skilled in the art. For example, treatment of a compound of the present invention with a suitable base or acid in a suitable solvent can yield the corresponding salt. The present invention relates to methods of treating or preventing viral infection, for example, an HIV infection, in a human, comprising administering to a human a therapeutically effective amount of a compound represented by formula (I), (11), or (III), or a pharmaceutically acceptable salt thereof, in combination with one or more therapeutic agents selected from the group consisting of nucleotide reverse transcriptase inhibitors, nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors, CCRS antagonists, CXCR4 antagonists, fusion inhibitors, maturation inhibitors and integrase inhibitors. The combination may be administered simultaneously or sequentially. The compounds represented by (1), (II) and (III) are particularly suitable for the treatment of prophylaxis of HIV infections and related conditions. The term treatment used herein may be extended to include the prophylaxis as well as treatment of established infections, symptoms and associated clinical conditions such as AIDS-related complex (ARC), Kaposi's sarcoma and AIDS dementia. Combination therapies involve the administration of a compound of the present invention or a pharmaceutically acceptable salt thereof and another pharmaceutically active agent. The active ingredient(s) and the pharmaceutically active agents may be administered simultaneously (i.e. at the same time), either in the same or different pharmaceutical compositions, or sequentially in any order. The amounts of the active ingredient(s) and pharmaceutically active agent(s) and their respective timings of administration will be selected to achieve the desired combined therapeutic effect. Examples of therapeutic agents include, but are not limited to, agents effective for the treatment of viral infections or related conditions. These agents include nucleoside transcriptase inhibitors, acyclic nucleoside phosphonates, such as (S)-1-(3-hydroxy-2-phosphonyl-methoxypropyl) cytosine (HPMPC), [[[2-(6-amino-9H-purin-9-yl)ethoxy]methyl]phosphinylidene] bis(oxymethylene)-2,2-dimethylpropanoic acid (bis-POM PMEA, adefovir dipivoxil), adefovir, [[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl]phosphonic acid (tenofovir), tenofovir disoproxil fumarate, and (R)-[[2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl]phosphonic acid. bis-(isopropoxycarbonyloxymethyl)10ester (bis-POC-PMPA); nucleoside reverse transcriptase inhibitors, e.g., 3'-azido-3'-deoxythymidine (AZT, zidovudine), 2',3'-dideoxycytidine (ddC, zalcitabine), 2',3'-dideoxyadenosine, 2',3'-dideoxyinosine (ddL, didanosine), 2',3'-didehydrothymidine (d4T, stavudine), (-)-c_is-1-(2-hydroxymethyl)-1,3-oxathiolan-5-yl)-cystosine (lamivudine), (-)-(2-(hydroxymethyl)-1,3-oxathiolan-5-yl)-5-fluorocytosine (FTC, emtricitabine), (-)-4-[2-amino-6-(cyclo- propylamine)-9H-purin-9-yl]-2-cycl10pentene-1-methane01 (abacavir), fozivudine tidoxyl, alovudine, aindoxovir, elvucitabine, apricitabine and festinavir (OBP-601); protease inhibitors, such as indinavir, ritonavir, nelfinavir, amprenaVir, saquinaVir, fosamprenavir, lopinavir, atazanavir, tipranavir, darunavir, bresanavir, palinavir, lasinavir, TMC-310911, DG-17 PPL-100, and SPI-256; non-nucleoside reverse transcriptase inhibitors (NNRTIs), such as nevirapine, delavirdine, efavirenz, GSK2248761 (IDX-12899), lersivirine (UK-453,061), rilpivirine (TMC-278), etravirine, loviride, iminenocal, oltipraz, capravirine, and RDEA-806; integrase inhibitors, such as raltegravir, elvitegravir, and JTK-656; CCR5 and/or CXCR4 antagonists, such as maraviroc, vicriviroc (Sch-D), TBR-652 (TAK-779), TAK-449, PRO-140, GSK706769, and SCH-532706; fusion inhibitors, such as enfuvirtide (T-20), T-1249, PRO-542, ibalizumab (TNX-355), BMS-378806 (EMS-806), BMS-488043, KD-247, 5-Helix inhibitors and HIV attachment inhibitors; and maturation inhibitors, such as bevirinate (PA-344 and PA-457). The present invention has a combination comprising a compound represented by the formula (I), or a pharmaceutically acceptable salt thereof, and or one or more therapeutic agents selected from the group consisting of lamivudine, abacavir, tenofovir, efavirenz, GSK2248761, lersivir, lopinavir, fosamprenavir and atazanavir. The present invention also has a combination comprising a compound represented by the formula (I), or a pharmaceutically acceptable salt thereof, and one or more therapeutic agents selected from abacavir, efavirenz or lopinavir. The present invention has a method for treating HIV infection, comprising administering to a subject a compound represented by formula (I), or a pharmaceutically acceptable salt thereof, and one or more therapeutic agents selected from the group consisting of lamivudine, abacavir, tenofovir, efavirenz, GSK2248761, lersivir, lopinavir, fosamprenavir, and atazanavir. The present invention has a method for treating HIV infection, comprising administering to a subject a compound represented by formula (I), or a pharmaceutically acceptable salt thereof, and one or more therapeutic agents selected from the group consisting of abacavir, efavirenz, and lopinavir. The present invention has a method for treating HIV infection, comprising administering to a subject a compound represented by formula (I), or a pharmaceutically acceptable salt thereof, and abacavir. The present invention has a pharmaceutical composition comprising a compound represented by formula (I), or a pharmaceutically acceptable salt thereof, and one or more therapeutic agents selected from the group consisting of lamivudine, abacavir, tenofovir, efavirenz, GS K224876 1 , lersivir, lopinavir, fosamprenavir, and atazanavir, together with a pharmaceutically acceptable carrier therefor. The present invention has a method for treating HIV infection, comprising administering to a subject a compound represented by formula (I), or a pharmaceutically acceptable salt thereof, and one or more therapeutic agents selected from the group consisting of abacavir, efavirenz, and lopinavir. A pharmaceutical composition comprising the therapeutic agent together with a pharmaceutically acceptable carrier therefor. The present invention has a pharmaceutical composition comprising a compound represented by the formula (I), or a pharmaceutically acceptable salt thereof, and abacavir together with a pharmaceutically acceptable carrier therefor. The present invention has a combination comprising a compound represented by the formula (H), F(II)13, or a pharmaceutically acceptable salt thereof, and or one or more therapeutic agents selected from the group consisting of lamivudine, abacavir, tenofovir, efavirenz, GSK2248761, lersivir, lopinavir, fosamprenavir, and atazanavir. The present invention also has a combination comprising a compound represented by the formula (H), or a pharmaceutically acceptable salt thereof, and one or more therapeutic agents selected from abacavir, efavirenz, and lopinavir. The present invention has a combination of a compound represented by the formula (H), or a pharmaceutically acceptable salt thereof, and abacavir. The present invention has a method for treating HIV infection, comprising administering to a subject a compound represented by the formula (11), or a pharmaceutically acceptable salt thereof, and one or more therapeutic agents selected from the group consisting of lamivudine, abacavir, tenofovir, efavirenz, GSK2248761, lersivir, lopinavir, fosainprenavir, and atazanavir. The present invention has a method for treating HIV infection, comprising administering to a subject a compound represented by the formula (11), or a pharmaceutically acceptable salt thereof, together with one or more therapeutic agents selected from the group consisting of abacavir, efavirenz, and lopinavir. The present invention has a method for treating HIV infection, comprising administering to a subject a compound represented by formula (H), or a pharmaceutically acceptable salt thereof, and abacavir. 14The present invention has a pharmaceutical composition comprising a compound represented by the formula (11), or a pharmaceutically acceptable salt thereof, and one or more therapeutic agents selected from the group consisting of lamivudine, abacavir, tenofovir, efavirenz, GSK2248761, lersiVirin, lopinavir, fosamprenavir and atazanavir, together with a pharmaceutically acceptable carrier therefor. The present invention has a pharmaceutical composition comprising a compound represented by the formula (H), or a pharmaceutically acceptable salt thereof, and one or more therapeutic agents selected from the group consisting of abacavir, efavirenz and lopinavir, together with a pharmaceutically acceptable carrier therefor. The present invention has a pharmaceutical composition comprising a compound represented by the formula (II), or a pharmaceutically acceptable salt thereof, and abacavir together with a pharmaceutically acceptable carrier therefor. The present invention has a combination comprising a compound represented by the formula (III), or a pharmaceutically acceptable salt thereof, and or one or more therapeutic agents selected from the group consisting of lainivudine, abacavir, tenofovir, efavirenz, GSK2248761, lersivir, 10pinavir, fosamprenavir, and atazanavir. The present invention also has a combination comprising a compound represented by the formula (III), or a pharmaceutically acceptable salt thereof, and one or more therapeutic agents selected from abacavir, efavirenz, and 10pinavir. has a combination. The present invention has a combination comprising a compound represented by the formula (III), or a pharmaceutically acceptable salt thereof, and abacavir. The present invention has a method for treating HIV infection, comprising administering to a subject a compound represented by the formula (111), or a pharmaceutically acceptable salt thereof, and one or more therapeutic agents selected from the group consisting of lamivudine, abacavir, tenofovir, efavirenz, GSK2248761, lersivir, lopinavir, fosamprenavir, and atazanavir. The present invention has a method for treating HIV infection, comprising administering to a subject a compound represented by the formula (111), or a pharmaceutically acceptable salt thereof, together with one or more therapeutic agents selected from the group consisting of abacavir, efavirenz, and 10pinavir. The present invention has a method for treating HIV infection, comprising administering to a subject a compound represented by the formula (III), or a pharmaceutically acceptable salt thereof, and abacavir. The present invention has a pharmaceutical composition comprising a compound represented by the formula (III), or a pharmaceutically acceptable salt thereof, and one or more therapeutic agents selected from the group consisting of lamivudine, abacavir, tenofovir, efavirenz, GSK2248761, lersivir, lopinavir, 16fosamprenavir, and atazanavir, together with a pharmaceutically acceptable carrier therefor. The present invention has a method for treating HIV infection, comprising administering to a subject a compound represented by the formula (III), or a pharmaceutically acceptable salt thereof, and one or more therapeutic agents selected from the group consisting of lamivudine, abacavir, tenofovir, efavirenz, GSK2248761, lersivir, lopinavir, 16fosamprenavir, and atazanavir, together with a pharmaceutically acceptable carrier therefor. The present invention has a pharmaceutical composition comprising a compound represented by formula (III), or a pharmaceutically acceptable salt thereof, and abacavir, together with a pharmaceutically acceptable carrier therefor. The present invention has combinations, methods of treatment and pharmaceutical compositions as described above, wherein a pharmaceutically acceptable salt represented by formula (1), (11) or (111) is a sodium salt. The present invention has combinations, methods of treatment and pharmaceutical compositions as described above, wherein one or more therapeutic agents is a pharmaceutically acceptable salt of said therapeutic agents, such as abacavir hemisulfate, fosamprenavir calcium, atazanavir sulfate, tenofovirdizoproxil sulfate, vicriviroc maleate or bevirimate dimeglumine. The present invention has combinations, methods of treatment and pharmaceutical compositions as described above, wherein the subject is a human. The present invention has combinations, methods of treatment and pharmaceutical compositions as described above, wherein the combination is 17 sequentially The present invention has combinations, methods of treatment and compositions having the features described above wherein the combination is administered simultaneously or sequentially. Compounds represented by formula (1), (II) and (111) can be produced by the methods described in WO 2006/116764 , US 61/193,634 ( WO2010/068253 ) or 61/193,636 ( WO2010/068262 ). Abacavir is disclosed in US Patent Nos. 5,034,394 ; 5,089,500 ; 6,294,540 ; 5,641,889 ; .840,990 ; 5,919,941 ; 5,808,147 ; 6,392,085 ; Lamivudine, US Patent Nos. 5,047,407; 7,119,202; 5,905,082; .696,254; 5,663,320; 5,693,787; 6,051,709; or 6,329,522. Tenofovir, US Patent No. 5,922,695; Efavirenz can be manufactured by the methods described in US Patent Nos. 5,935,946; 5,977,089; 6,043,230,6,069,249. or 6,939,964. GSK2248761 can be produced by methods described in US Patent No. 7,534,809. Lesivirin can be produced by methods described in US Patent No. 7,109,228. Lopinavir can be produced by methods described in US Patent No. 5,914,332. Fosamprenavir can be produced by methods described in US Patent No. 6,436,989; Atazanavir can be produced by the methods described in US Patent Nos. 5,849,911 or 6,087,383. In one aspect of the invention, a compound represented by formula (I), (11) or (111) or a pharmaceutically acceptable salt thereof can be formulated into compositions with one or more therapeutic agents. The composition can be a pharmaceutical composition comprising a compound represented by formula (I), (11) or (111) or one or more therapeutic agents, and a pharmaceutically acceptable carrier, adjuvant or vehicle. In one embodiment, the composition includes an amount of a combination effective to treat or prevent a viral infection, such as an HIV infection, in a biological sample or a patient. In another embodiment, the combinations and pharmaceutical compositions thereof, comprising an amount of a combination of the present invention effective to inhibit viral replication or to treat or prevent a viral infection or disease or disorder, such as an HIV infection, and a pharmaceutically acceptable carrier, adjuvant or vehicle, can be formulated for administration to a patient, such as for oral administration. The present invention has compositions of the invention for use in medical therapy, such as for the treatment or prophylaxis of a viral infection, such as an HIV infection, and related conditions. In particular, the compounds of the invention are used to treat AIDS and related clinical conditions such as AIDS-related complex (ARC), progressive disseminated lymphadenopathy (PGL), Kaposi's sarcoma, thrombocytopenic purpura, AIDS-related neurological conditions such as AIDS dementia complex, multiple sclerosis or tropical paraparesis, and anti-HIV antibody-positive and HIV-positive states, including such conditions in asymptomatic patients. In another aspect, the present invention provides a method of treating or preventing the symptoms or effects of a viral infection in an infected patient, such as a mammal, comprising administering to the patient a pharmaceutically effective amount of the combination of the invention. According to one aspect of the invention, the viral infection is a retroviral infection, in particular an HIV infection. The present invention also includes the use of a combination of the invention in the manufacture of a medicament for simultaneous or sequential administration to a subject for treating a viral infection, in particular an HIV infection. The present invention also provides a method for treating a clinical condition in a patient, e.g., a mammal, including a human, whose clinical condition includes those assessed above, comprising treating the patient with a pharmaceutically effective amount of a compound of the invention. The present invention also includes a method for the treatment or prophylaxis of any of the above diseases or conditions. 20 The compounds of the present invention can be administered with an agent known to inhibit or reduce the metabolism of the compounds, e.g., ritonavir. Accordingly, the present invention provides a method for the treatment or prophylaxis of a disease by administering a compound of the present invention in combination with a metabolic inhibitor, as described above. This combination may be administered simultaneously or sequentially. In general, a general suitable dose for each of the above-mentioned conditions will be in the range of 0.01 to 250 mg per kilogram body weight of the recipient (e.g., human) per day; 0.1 to 100 mg per kilogram body weight per day; 1 to 30 mg per kilogram body weight per day; and 0.5 to 20 mg per kilogram body weight per day. Unless otherwise stated, all weights of the active ingredients are calculated as the parent compound represented by formula (1), (11) or (111) and other therapeutic agents. For their salts, the weights will be increased proportionally. The desired dose may be presented as one, two, three, four, five, six or more sub-doses administered at appropriate intervals throughout the day. In some cases, the desired dose may be given on alternate days. These sub-doses may be administered in unit dosage forms containing, for example, 1 to 2000 mg; 5 to 500 mg; 10 to 400 mg; 20 to 300 mg of each active ingredient per unit dosage form. Combinations may be administered so as to achieve peak plasma concentrations of each active ingredient. While it is possible to administer the active ingredients alone, it is preferable to present them as a pharmaceutical composition. The compositions of the present invention comprise an active ingredient, as defined above, together with one or more acceptable carriers and one or more additional therapeutic agents. Each carrier must be acceptable in the sense of being compatible with the other components of the composition and not injurious to the patient. The pharmaceutical compositions may be administered orally, rectal, nasal, topical (including transdermal, buccal and sublingual), vaginal or parenterally (including subcutaneous, intramuscular, intravenous, intradermal and intravitreal). The compositions may be conveniently presented in unit dosage form and may be prepared by methods well known in the art of pharmacy. These methods include the step of bringing the active ingredient into association with a carrier constituting one or more accessory ingredients. Generally, the compositions are prepared by homogeneously and thoroughly combining the active ingredients with liquid carriers or finely divided solid carriers or both and then shaping the product if necessary. The present invention also includes a pharmaceutical composition of the previously described nature wherein a compound of the present invention or a pharmaceutically acceptable derivative thereof and another therapeutic agent are presented separately as a kit of parts. Compositions suitable for transdermal administration may be presented as discrete patches adapted to remain in intimate contact with the recipient's epidermis for an extended period of time. Such patches contain the active compound as appropriate 1) in an aqueous solution, optionally buffered, or 2) dissolved and/or dispersed in an adhesive 22 or 3) dispersed in a polymer. A suitable concentration of the active ingredient is from about 1% to 25%, preferably from about 3% to 15%. As a particular possibility, the active ingredient can be delivered from the patch by electrotransport or iontophoresis, as generally described in Pharmaceutical Research 3(6), 318 (1986). Pharmaceutical compositions suitable for oral administration of the present invention may be presented as discrete units such as capsules, caplets, capsules or tablets, each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous or nonaqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or paste. A tablet may be manufactured by compression or shaping, optionally with one or more accessory ingredients. Compressed tablets may be prepared in a suitable machine by mixing the active ingredients in a free-flowing form such as a powder or granules, optionally with a binder (e.g. povidone, gelatin, hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (e.g. sodium starch glycolate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent. Shaped tablets may be manufactured by mixing the moistened powdered compound with an inert liquid diluent and shaping in a suitable machine. The tablets may optionally be coated or scored, and may be formulated to provide slow or controlled release of the active ingredients, for example hydroxypropylinethyl cellulose, in varying proportions to provide the desired release profile23. The tablets may optionally be provided with an enteric coating to provide release in parts of the intestine other than the stomach. Pharmaceutical compositions suitable for topical administration in the mouth include lozenges containing the active ingredients in a flavoured delight, usually sucrose and acacia or tragacanth; lozenges containing the active ingredients in an inert base such as gelatin and glycerin or in sucrose and acacia; and mouthwashes comprising the active ingredients in a suitable liquid carrier. Pharmaceutical compositions suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or sprays. The pharmaceutical compositions may contain, in addition to the active ingredient, such carriers as are known in the art. Pharmaceutical compositions for rectal administration may be presented as a supernatant with a suitable carrier, for example cocoa butter or a salicylate or other substances commonly used in the art. Suppositories can conveniently be constructed by mixing the active compound with a softened or dissolved carrier(s) followed by cooling and shaping in a mold. Pharmaceutical compositions suitable for parenteral administration can include aqueous and nonaqueous isotonic sterile injection solutions, which may contain antioxidants, buffers, bacteriostats and solvents which render the pharmaceutical composition isotopic with the blood of the intended recipient; aqueous and nonaqueous sterile suspensions, which may contain suspending agents and thickening agents; and liposomes or other microparticulate systems designed to target the compound to blood components or to one or more organs. Pharmaceutical compositions may be presented in unit-dose or multi-dose sealed containers, e.g. ampoules and vials, and may be stored in a freeze-dried (lyophilized) state requiring only the addition of a sterile liquid carrier, e.g. water, for injection immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the type previously described. Unit-dose pharmaceutical compositions include compositions containing a daily dose or a daily subdose or an appropriate fraction thereof of the active ingredients as previously described. The pharmaceutical compositions of the present invention may be presented in a single pack, e.g. a blister pack, in patient packs containing one or more lines of treatment. It will be understood that administration of the combination of the invention via a single patient pack or via patient packs of each composition is an additional feature of the invention. It is to be understood that in addition to the components specifically mentioned above, the pharmaceutical compositions of the invention may contain other agents conventional in the art with respect to the type of pharmaceutical composition in question, for example, those suitable for oral administration may contain additional agents such as sweeteners, thickeners and flavoring agents. 25 Reference Examples Reference Example 1: Biological Activity Assays Method Antiviral HIV activity was measured in the human T-cell leukemia virus (HTLV-1) transformed cell line MT-4 by a tetrazolium-based colorimetric procedure. Aliquots of test compounds were diluted vertically across a deep-well master assay plate in medium (RPMI 1640, 10% v/v foetal bovine serum (FBS), and 10 µg/mL gentamicin) at concentrations approximately 40-fold higher than the final assay concentration. Serial dilutions were made at either 1:2 or 1:3.16. HIV inhibitors were diluted horizontally across the master assay plates at concentrations also approximately 40-fold higher than the final assay concentration. Small aliquots of both vertically diluted and horizontally diluted compounds were combined into daughter plates using an automated 96-well pipetting system (RapidPlate-96, Zymark Corp.). Checkerboard type dilutions were arranged such that each concentration of test compound was tested in the presence and absence of each concentration of HIV inhibitors. Anti-HIV activity tests were performed in triplicate or more of each combination. Exponentially growing MT-4 cells were harvested in a Jouan centrifuge (Model CR 4 12) and centrifuged at 1,000 rpm for 10 min. Cell pellets were resuspended in fresh medium (RPMI 1640, 20% v/v PES, 20% v/v IL-2, and 1026 ug/mL gentamicin) to a density of 1.25 x 106 cells/mL. Aliquots of cells were infected by the addition of HIV-1 (strain IIIB) diluted to give a multiplicity of viral infection (MOI) of 73 pfU per 1 X 104 cells. A similar aliquot of cells was diluted with medium to provide a virus-free infected control. Cell infection was allowed to proceed at 37°C for 1 h in a humidified 5% CO2 tissue culture oven. After 1 h of incubation, the virus/cell suspension was added to each well of the plates containing the prediluted compounds. The plates were then placed in a humidified 5% CO2 tissue culture oven for 5 days. At the end of the incubation period, 40 μL of CellTiter 96 MTS reagent (Promega no. G3581) was added to each well of the incubation plate. Plates were incubated at 37°C for 2 to 3 hours to allow color development. O.Y. was measured at 492 nM using a microplate absorbance reader (Tecan #20-300). The virus used was HIV-1 strain IIIB, a wild-type laboratory strain, Virus titer = 6.896 E4 TCID50/ml. Data Analysis Although some assay formats may theoretically miss antagonism due to combination cytotoxicity, the approach described here should not miss an antagonistic effect. The MT-4 cell assay uses MTS, a tetrazolium-based staining reagent, for counting, where changes in optical density (OD)27 of the reagent are used to estimate the total cell number remaining after treatment. The final MT-4 cell count may be reduced by two effects. First, HIV-induced cytotoxicity may occur when HIV kills more than 75% of MT-4 cells within 5 days of infection. Second, compound-induced cytotoxicity may occur when the compound directly kills MT-4 cells or inhibits cell growth within 5 days of infection in either infected or uninfected cells. In either of these cases, OD is low relative to infected cells protected by anti-HIV-1 compounds or to untreated, uninfected control cells. Since both cytotoxic effects and antagonism of anti-HIV activity will result in low O.Y., an antagonistic effect due to combination cytotoxicity will not be missed, but synergistic combinations may be underestimated. Combination cytotoxicity was assessed in the assay by comparing wells containing uninfected MT-4 cells in assay plates containing the highest concentration of test compound or comparator compound with wells containing HIV-1 infected MT-4 cells under the respective highest combination concentrations. For each of these values, there was one well per assay plate, thus at least 3 wells per combination assay. Although they do not include a forinal combination cytotoxicity analysis, the ratio of the compound in the combinations to the compound alone provides a measure of the compound combination cytotoxicity at the concentrations examined. The interaction of each pair of compound combinations was analyzed by the methods described by Selleseth, D. W. et al. (2003) in Antiinicrobial Agents and Chemotherapy 47:1468-71. Synergy and antagonism are defined as deviations from the drop additivity that occur when two drugs interact as if they were the same drug. Mean deviations from additivity between -0.1 and -0.2 indicate weak synergy, while values approaching -0.5 indicate strong synergy of the interaction. On the contrary, positive values between 0.] and 0.2 indicate a weak antagonism between the treatments. ResultsA compound represented by formula (1) was found to be additive with raltegravir, adefovir and maraviroc and was not affected by the presence of ribavirin. A compound represented by formula (1) was found to be synergistic with stavudine, abacavir, efavirenz, nevirapine, lopinavir, amprenavir, enfuvirtide. 29REFERENCES CITED IN THE DESCRIPTIONThis list of references referred to by the applicant is for the assistance of the reader only and does not form part of the European Patent Document. Although great care has been taken in the compilation of references, errors or omissions cannot be excluded, and the EPO accepts no liability in this regard. Patent documents cited in the specification: i WO 2009007441 A [0009] - wo 2006116764 A [0049] i US 61193634 B [0049] . wo 2010068253 A [0049] . us 61193636 B [0049] - wo 2010068262 A [0049] i US 5905082 A [0051] i us 5696254 A [0051] - US 5663320 A [0051] - us 5693787 A [0051] . us 6051709 A [0051] - us 6329522 B [0051] - us 5034394 A [0050] - us 5089500 A [0050] . US 6294540 B [0050] ~ US 5641889 A [0050] - US 5840990 A [0050] - US 5919941 A [0050] - US 5808147 A [0050] - US 6392085 13 [0050] - US 6448403 B [0050] ~ us 5917041 A [0050] - 118 6087501 A [0050] . US 5917042 A [0050] US 6555687 B [0050] - US 6552193 B [0051] - US 7119202 B [0051]Unpatented literature mentioned in the specification:- US 5922695 A [0052] . us 5935946 A [0052] . US 5977089 A [0052] . us 6043230 A [0052] - us 6069249 A [0052] . US 5519021 A [0053] - US 5663169 A [0053] . us 5811423 A [0053] - us 6555133 B [0053] . us 6639071 B [0053] c us 6939964 B [0053] . us 7534809 B [0054] - us 7109228 B [0055] . us 5914332 A [0056] 0 us 6436989 B [0057] - us 6514953 B [0057] . us 6281367 B [0057] - us 5849911 A [0058] . US 6087383 A [0058]' A Phase IIb Pilot Study to Assess the Antiviral Activity of GSK1349572 Containing Regimen in Antireteroviral SELLESETH, D.W. et al. Antimicrobial Therapy (ART)-Experienced. HIV-l-Agents and Chemotherapy, 2003, vol. 47, infected Adult Sub jects With Raltegravir 1468-71 [0084]Resistance, January 2010 [0008]0 Pharmaceutical Research, 1986, vol.3 (6), 318 [0070] TR TR TR

Claims (1)

1.